Schizophrenia (SCZ) is accompanied by impairment in a variety of cognitive domains, including working memory and executive function. The cognitive impairment is correlated with day-to-day function and has prognostic value, so it is important to understand its basis. Accumulating evidence implicates exposure to neurotropic viruses, such as herpes simplex virus 1 (HSV1) and human cytomegalovirus (HCMV), in cognitive impairment. These herpesviruses are ubiquitous. The question arises: How could these common viruses cause cognitive impairment in only a subset of those infected? Some complex gene-environment (virus) interactions may shed light on this paradox. Both viruses have evolved sophisticated immunoevasion strategies. One strategy involves encoding Fcy receptor (FcyR)-like proteins that interfere with Fcy-mediated host immunosurveillance mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC). Results of investigations by us, and others, show that alleles of a major gene complex of the immune system, GM allotypes, modulate this strategy. GM allotypes are predominantly expressed in the Fc region of immunoglobulin y chains. Our results show that IgG1 proteins expressing particular GM alleles have higher affinity for the viral FcyR than those expressing other alleles. We have recently shown that the high affinity GM allele is also associated with low antibody responsiveness to HCMV glycoprotein B. Based on these and other observations we hypothesize that GM genes are effect modifiers of HCMV/HSV1-associated cognitive impairment in patients with SCZ and the underlying mechanisms include their modulating influence on the viral immunoevasion strategies and their contribution to the anti-HCMV/HSV1 antibody responses. The following specific aims will test our hypothesis: 1) Determine if particular GM alleles are associated with cognitive variation in SCZ patients. Subjects expressing the high affinity (to viral FcyR) Fc (GM) allele would be more likely to have their Fc domains scavenged, thereby reducing their immunological competence to eliminate the virus through ADCC and other Fc-mediated effector mechanisms (e.g. complement-dependent cytotoxicity and phagocytosis). Consequently, they would be expected to have higher degree of virally-induced/spurred cognitive impairment than those expressing the low affinity allele; 2) Determine if the magnitude of antibody responsiveness to particular HSV1 and HCMV proteins is restricted by GM alleles in patients with SCZ. Glycoprotein B (gB) is conserved among the herpesvirus family members because of its role in infectivity, viral attachment and entry. We will quantitate antibody responses to HSV1-gB and HCMV-gB proteins in the sera of SCZ patients. We will genotype the subjects' DNA for several GM alleles and determine if they are associated with the magnitude of anti-HCMV and anti-HSV1 antibody responses. This proposal opens a new avenue of investigation towards our understanding of the immunogenetic etiology of cognitive impairment in SCZ, and the results obtained may help devise novel immunotherapeutic interventions in this devastating disorder.